Project Summary Anxiety disorders are the sixth leading cause of worldwide disability and the most common mental illness, with a lifetime prevalence affecting approximately 29% of the population. Anxiety Sensitivity (AS) refers to an individual?s fear of experiencing anxiety-related symptoms (e.g., dyspnea or heart palpitations) and is a core construct underlying the initiation and maintenance of pathological anxiety. Recent evidence suggests that reducing AS may be critical for the prevention and treatment of anxiety across diagnostic categories. Exposure therapy, an important component of cognitive behavioral therapy (CBT), is one of the most effective treatments for reducing AS, and has been shown to improve symptoms across a number of different anxiety disorders. Meta-analyses reveal an approximately 50% treatment response rate, with the remaining half of patients showing either no response (~35%) or dropping out of treatment early (~15%). Unfortunately, there is a paucity of research exploring which variables predict treatment outcome and currently no tests for predicting which patients would benefit the most from exposure therapy. The current proposal will employ a carbon dioxide (CO2) habituation paradigm (CHP), a safe and noninvasive physiological test for inducing a transient state of anxiety. In phase 1 of the proposal (years 1-2), we will measure how an individual?s level of anxiety changes across repeated exposures to single vital capacity inhalations of 35% CO2, and in phase 2 (years 3-5), we will determine whether an individual?s degree of habituation to CO2 predicts treatment success following 10 weeks of exposure therapy. This proposal aims to test the CHP in a sample of treatment-seeking subjects with high levels of AS (n=70; hAS) and a comparison group of healthy participants with normal levels of AS (n=20, nAS). Participants will undergo the CHP twice (completed on separate days) and measures of reactivity and habituation will be calculated across a number of behavioral, subjective, and physiological indices of anxiety. A baseline fMRI scan (provided by the Research Core) will be used to relate individual differences in reactivity and habituation on the CHP to specific patterns of brain activation and connectivity. In the first aim, we predict that hAS subjects (relative to nAS) will experience significantly more anxiety during the CHP, helping to establish the primary variables (behavioral, subjective, and physiological) that distinguish healthy from anxious participants on the CHP. In the second aim, hAS subjects will undergo 10 weeks of exposure therapy and we predict that subjects who exhibited the most between-session habituation during the CHP will benefit the most from exposure therapy, whereas subjects with deficient CO2 habituation and heightened CO2-induced avoidance and escape behavior will show the poorest treatment outcomes. The findings will reveal whether the CHP is a useful tool for predicting which patients would be the best candidates for exposure therapy.